Obsessive-Compulsive Disorder: Neurobiology and the Latest in Treatment

Derick E. Vergne, MD


May 17, 2017

In This Article

Neurotransmitter Systems in OCD

Obsessions are persistent, cyclical, and redundant. Compulsions justify the existence of the obsessions, and obsessions are "magically" but only momentarily quelled by the compulsion. As discussed, the brain's basic organization revolves around parallel fronto-striato-thalamo-cortical loops that foster efficient information processing. Glutamate, the major excitatory neurotransmitter in the brain, is the primary driving force of the circuit.

One can understand glutamate by understanding that when glutamatergic transmission gets out of control, it causes uncontrollable seizures. In fact, in patients with seizure disorder, an excessive glutamate-mediated discharge provokes symptoms that are controlled with anticonvulsants, which reduce glutamate neurotransmission.[16] If OCD results from overactive or dysfunctional CSTC circuitry, and the circuit's main activity generator is glutamate, then it is not farfetched to conceptualize OCD as a type of "seizure disorder." In fact, cortical hyperexcitability is a trademark of OCD. Moreover, the rationale behind anticonvulsants as putative therapeutic agents[17,18] relates to the hypothesis that decreasing, balancing, or effectively modulating glutamate neurotransmission normalizes the cortical glutamate tone connecting to the striatum (the initial input of the CSTC circuit is from cortex to the striatum, with glutamate as its main excitatory neurotransmitter),[18] thereby decreasing the redundancy of information processing that can lead to obsessions and compulsions.

Some currently available antiglutamatergic medications include lamotrigine, topiramate, and gabapentin (at high doses). These medication options could serve as adjunct treatments for OCD, but not as sole options.

Dopamine is another key neurotransmitter related to OCD pathophysiology because of its heterogeneous function in the brain and, for our purposes, its receptor profile within the CSTC circuit. As described earlier, the striatum connects to the thalamus by direct and indirect pathways, and their balancing activity determines effective information flow. The direct pathway contains dopamine 2 (D2) receptors, whereas the indirect pathways contain mostly D1 receptors.[7] The difference between these pathways, in terms of excitation (direct pathway) and inhibition (indirect pathway), points to the role of dopamine in mediating the proper balance between pathways and the eventual organized flow of information from the thalamus to the cortex.

Clinical translational studies have shown consistent involvement of the dopaminergic system in the mediation of perseverations and obsessions. For example, dopamine agonists (stimulators such as amphetamines, for example) can have pro-OCD effects and lead to the development of tics, perseverations, and compulsive behavior.[19] In contrast, D2 blockers, such as low-dose risperidone, have been shown to reduce the intensity of obsessions and compulsions, particularly when used as adjunctive treatment to serotonergic agents.[20] Serotonergic agents, such as selective serotonin reuptake inhibitors (SSRIs), continue to demonstrate efficacy in OCD, although their effectiveness over the long term has not been demonstrated.


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